Pharmaceutical preparation containing oxycodone and naloxone

ABSTRACT

The invention concerns a storage stable pharmaceutical preparation comprising oxycodone and naloxone for use in pain therapy with the active compounds being released from the preparation in a sustained, invariant and independent manner.

The invention concerns a storage-stable pharmaceutical preparationcomprising oxycodone and naloxone.

The treatment of severe pain which results from diseases such as cancer,rheumatism and arthritis is central to the treatment of these diseases.The range of pain felt by tumor patients comprises pain of theperiosteum and of the bone itself, as well as visceral pain and pain insoft tissues. All such pain forms render the daily life of patientsintolerable and often lead to depressive states. Successful pain therapyresulting in a lasting improvement of quality of life for the patientsis therefore equally important to the success of a comprehensivetherapy, as is the treatment of the actual causes of the disease.

Regarding the importance of a successful pain therapy, the World HealthOrganization (WHO) has developed a 4-step model for the treatment ofpatients with tumor pain. This model has proven to be effective in dailyroutine practice and can be extended to patients suffering from chronicpain or pain forms which result from diseases other than cancer.Depending on the intensity, quality and localization of pain, four stepsare distinguished during this therapy, with each next step beingindicated if the effect of the pain relief agent used until then is nolonger sufficient (Ebell, H. J.; Bayer A. (Ed.): Die Schmerzbehandlungvon Tumorpatienten, Thieme 1994 (Supportive Malβnahmen in der Onkologie,Band 3) and Zech, D.; Grond, S.; Lynch, J.; Hertel, D.; Lehmann, K.:Validation of World Health Organisation Guidelines for Cancer PainRelief: a 10-year prospective study, Pain (1995), 63, 65-76). Accordingto this 4-step model of the WHO, opioid analgesics take a central rolein treating pain. The group of opioid analgesics comprises, besidesmorphine which represents the prototype of these pharmaceutically activeagents, also oxycodone, hydromorphone, nicomorphine, dihydrocodeine,diamorphine, papaveretum, codeine, ethylmorphine, phenylpiperidine andderivatives thereof; methadone, dextropropoxyphene, buprenorphine,pentazocine, tilidine, tramadol and hydrocodone. The ATC-Classification(Anatomical Therapeutic Chemical Classification) of the WHO indicateswhether the pharmaceutically active agent represents an opiod analgesic,or not. The pronounced pain-relieving effect of opioid analgesics is dueto the imitation of the effect of endogenous, morphine-like actingsubstances (“endogenous opioids”), whose physiological function is tocontrol the reception and processing of pain stimuli.

Opioids repress the propagation of pain stimuli. Besides the immediateinhibition of neuronal excitatory signal transduction in the spinal cordcaused by opioids, an activation of such nerve tracts is relevant, whichproject form the brainstem into the spinal cord. This activation resultsin an inhibition of pain propagation in the spinal cord. Moreover,opioids limit the pain reception of the thalamus and by affecting thelimbic system they influence the affective pain evaluation.

Opioid receptors are found at different sites in the body. Receptors ofthe intestine and brain are of particular importance for pain therapy byopioids, especially as their occupation results in different sideeffects.

Opioid analgesics are considered to be strong agonists if they bind withhigh affinity to opioid receptors and induce a strong inhibition of painreception. Substances that also bind with high affinty to opioidreceptors, but that do not provoke a reduction of pain reception andwhich thereby counteract the opioid agonists, are designated asantagonists. Depending on the binding behaviour and the inducedactivity, opioids can be classified as pure agonists, mixedagonists/antagonists and pure antagonists. Pure antagonists comprise,for example, naltrexone, naloxone, nalmefene, nalorphine, nalbuphine,naloxoneazinen, methylnaltrexone, ketylcyclazocine, norbinaltorphimine,naltrindol, 6-13-naloxol und 6-13-naltrexol (Forth W.; Henschler, D.;Rummel W.; Starke, K.: Allgemeine und Spezielle Pharmakologie undToxikologie, 7. Auflage, 1996, Spektrum Akademischer Verlag, HeidelbergBerlin Oxford).

Due to their good analgesic efficiency compounds such as oxycodone,tilidine, buprenorphine und pentazocine, have been used in the form ofmedicaments for pain therapy. Medicaments such as Oxigesic® (whereinoxycodone is the analgesic active compound) und Valoron® (whereintilidine is the analgesic active compound ) have proven valuable forpain therapy.

However, use of opioid analgesics for pain therapy might go along withundesirable side effects. Thus, long-term use of opioid analgesics canlead to psychological and physical dependence.

Especially the physical dependence of patients suffering from pain toopioid analgesics leads to the development of tolerance, meaning thatupon extended intake, increasingly higher doses of the pain relievingagent have to be taken by the patient, in order to experience painrelief. The euphoregenic effect of opioid analgesics often leads to theabuse of pain relievers. Drug abuse and psychological dependence are acommon phenomenon, especially among teenagers. These dangerous effectsare especially caused by the substances with strong analgesic capacity,and can range from undesired habituation to fully developed addiction.However, these substances are legitimately used for medical purposes andmedicine cannot do without them.

Besides the mentioned disadvantages, the use of potent opioid analgesicsfor pain therapy often also lead to undesirable side effects, such asobstipation, breath depression, sickness and sedation. Less frequently,the urge or the disability to pass water are observed. Differentattempts have been made to counteract the habituation processes and theother side effects occurring during pain therapy. This can be done, e.g.by traditional treatment methods. In the case of drug addiction thismight be a drug withdrawal treatment, and in the case of obstipation,this might be done by administration of laxatives.

Other attempts aim at minimizing the addictive and habituation formingpotential of opioid analgesics, as well as their other side effects bythe administration of antagonists which counteract the opioid analgesic.Such antagonists might be naltrexone or naloxone.

There have been numerous proposals and suggestions, how the applicationof the aforementioned active compounds could be used to avoid undesiredhabituation and dependence, or even addiction.

U.S. Pat. Nos. 3,773,955 und 3,966,940 suggested to formulate analgesicsin combination with naloxone, in order to prevent dependence-promotingeffects such as euphoria and the like, upon parenteral application. Theavoidance of side effects such as obstipation has not been addressed.

To limit the parenteral abuse of oral application forms, U.S. Pat. No.4,457,933 suggested the combination of morphine with naloxone in definedranges. The avoidance of side effects such as obstipation has also notbeen mentioned.

U.S. Pat. No. 4,582,835 describes, again in order to avoid abuse, apreparation comprising a combination of buprenorphine and naloxone, thatis to be administered either parenterally or sublingually.

European application EP 0 352 361 A1 concerns the treatment ofobstipation during pain therapy by the oral application of an opioidanalgesic and one antagonist, with the antagonist being a pro-drug formof either naltrexone or naloxone. Avoidance of abuse of the opioidanalgesic is not an issue in this application.

German patent application DE 43 25 465 A1 also concerns the treatment ofobstipation during pain therapy using a preparation which comprises anopioid analgesic and an antagonist. The characterizing feature of thisdisclosure is that the antagonist which can be naloxone, has to bepresent in higher amounts than the opioid analgesic which is preferablymorphine. This is to ensure that the antagonist unfolds itsanti-obstipation effect without reducing the analgesic activity of theagonist. The avoidance of abuse of the opioid analgesic is not an issuein this application.

In order to avoid side effects such as obstipation and breath depressionduring pain therapy, preparations have been introduced on the marketwhich can be taken orally and comprise an opioid analgesic and theopioid antagonist, naloxone. The medicament Talwin® of Windrop/Sterlingcomprises pentazocine and naloxone. The medicament Valoron® of Gödekecomprises a tilidine-naloxone combination.

Besides the potent analgesic effect, the reduction of addictivepotential and the avoidance of side effects, medicaments usable for asuccessful pain therapy should provide for additional characteristics.

Generally, medicaments have to be formulated in a way that the activecompounds are stable as long as possible, under standard storageconditions. Medicaments have also to be formulated in a way that theintended release profiles of the active compounds do not change uponlong-term storage.

Additionally, (also in the case of agonist/antagonist-combinations) therelease profile of each single active compound should be selectable asrequired. The measures applied in order to achieve this should nothamper or even prevent that the release profiles of additional activecompounds (e.g. in the case of combinations of different activecompounds) can be chosen as required. Consequently, there should be nomutual dependency of the release profiles.

Medicaments suitable for pain therapy should either contain the activecompounds in such amounts or be formulated in such ways that they haveto be taken by the patients only rarely. The easier the applicationscheme for a pain reliever is, and the more evident it is for thepatient why and how often he should take which tablet, the more exactlyhe will adhere to the physician's orders. The necessity to take the painreliever only infrequently, will result in a high willingness of thepatient to take the pain reliever (compliance).

Through the use of so called sustained-release formulations, i.e.formulations of medicaments from which the active compounds are releasedover an extended period of time, it has been tried to lower thefrequency by which pain relieving medicaments have to be taken, andthereby to increase the compliance of patients. Such sustained-releaseformulations also make sense in that the sustained release of an opioidanalgesic reduces the addictive potential of this active compound.

This is due to the fact that the addictive potential of an activecompound is not defined by the compound itself, but rather by the way itis administered and the pharmaco-dynamics resulting therefrom. Besidesthe psychotropic effect of an opioid, the rate by which the brainencounters an opioid, is more decisive criterion for the risk ofdependency than the active compound itself (Nolte, T.: STK-Zeitschriftfür angewandte Schmerztherapie, 2001, Vol. 2).

The medicament Oxigesic® of Purdue is a preparation from which theopioid analgesic oxycodone is released in a sustained manner. Due tothis formulation, the frequency by which the medicament has to be takenas well as the addictive potential is lowered, however the side effectsremain and the danger of developing addiction cannot be excluded, asOxigesic® does not contain opioid-antagonists.

According to the already mentioned European patent application EP 0 352361 A, neither the opioid analgesic nor the antagonist are formulated tobe released in a sustained manner. Accordingly, the time period duringwhich such preparations are effective is limited and preparations haveto be taken multiple times per day. The desired compliance of thepatient is not achieved. This application also does not disclose theadvantages of formulations of preparations that are characterized by atime-stable and independent release of the active compounds. The storagestability of such preparations is also not addressed by this disclosure.

German patent application DE 43 25 465 A1 discloses formulationsaccording to which obstipation occurring during pain therapy isprevented by the sustained release of the opioid agonist while theantagonist, which is present in excess must not be released in asustained manner. Due to the high First-Pass-Effect of naloxone,comparably large amounts of this compound have therefore to be used.This application discloses neither the advantages nor the formulationsof preparations, which are characterized by time-stable and independentrelease of the active compounds. The storage stability of suchpreparations is also not an issue of this disclosure. A doctor usingpreparations according to this disclosure has therefore to carry outextensive titration experiments each time he wants to increase thedosage.

The company Gödeke offers, under the trademark Valoron®, a pain relieverthat comprises a tilidine-naloxone-combination. According to the productliterature, a formulation is used from which both active compounds arereleased in a sustained manner. The matrix used comprises a relevantpart of water-swellable material (HPMC) and has therefore to beconsidered as a swellable (and possibly partially erosive) diffusionmatrix. A disadvantage of this known formulation is that tilidine andnaloxone, given identical mass ratios but different absolute amounts,show different release profiles. The release rates of the agonist andthe antagonist are not independent from each other, which is probablydue to the sustained release formulation used. Accordingly, it isnecessary for the physician to carry out extensive titration experimentsfor each individual patient if he wants to increase the dosage eventhough he does not change the mass ratio of tilidine:naloxone, as hecannot assume that the release profiles of both components will remainconstant. The range of therapeutically usable amounts of the analgesicthat are available to the doctor is therefore limited.

It is one of the objectives of the present invention to provide apharmaceutical preparation for pain therapy that, given a high analgesicactivity, is characterized by a reduced abuse potential and reduced sideeffects, said preparation also being characterized by a reducedadministration frequency and therefore providing increased compliance,as well as the ability for individual adaptation of the dosage for eachpatient. A further objective of the present invention is to provideformulations for pharmaceutical preparations usable in pain therapy thatmake sure that the active compounds of said pharmaceutical preparationsare stable over a long storage time, and that the release of the activecompounds remain reproducibly invariant and independent from each othereven after long-term storage.

The feature combination of the independent claim serves to attain these,and further objectives which can be noted from the ensuing descriptionof the invention. Preferred embodiments of the invention are defined inthe subclaims.

According to the invention, the objectives are attained by providing astorage-stable pharmaceutical preparation comprising oxycodone andnaloxone wherein said preparation is formulated such that the activecompounds are released in a sustained, invariant and independent manner.

By the combination of oxycodone (in an analgesically effective amount)and naloxone it is ensured that preparations according to the inventionshow an efficient analgesic activity and that at the same time, commonside effects such as obstipation, breath depression and development ofaddiction are suppressed, or at least significantly reduced. The matrixformulation, which is stable over extended periods of time, ensurespermanently that agonist as well as antagonist are always released inpredetermined percentages and that their release rates do not influenceeach other. Thereby, abuse of the medicament, which requires that theoxycodone can selectively be extracted from the formulation, isprevented. The formulation according to the invention disables selectiveextraction of the agonist from the preparation without the correspondingamount of the antagonist, independent of the absolute and relativeamounts of agonist and antagonist chosen.

Moreover, the formulation of a medicament according to the inventionensures that, given identical relative amounts, the active compoundsshow equal release profiles, independent of the absolute amount present.Such an independent release behaviour provides a wide range of useableabsolute amounts of the analgesic active substance to the physician,given that the optimal agonist/antagonist ratio is known. Thus, it ispossible to comfortably adjust the dosage for each individual patient,either by a step-wise dosage increase or, if necessary, a step-wisedosage reduction. This ability to adjust the dosage for the individualpatient is extremely useful from a medical point of view.

The characterizing features of the present invention, which comprise thesustained, invariant and independent release of the active compoundsensure additionally that pharmaceutical preparations produced accordingto the invention are characterized by a low administration frequency, sothat high patient compliance is achieved. Furthermore, preparationsaccording to the invention allow the doctor to adjust the dosage forindividual patients. Preparations according to the invention enable useover a broad range with respect to the useable absolute amounts of theactive compounds and ensure that the active compounds, even afterlong-term storage, become effective with equal release profiles.

According to the present invention, sustained release of activecompounds means that pharmaceutically active substances are releasedfrom a medicament over a longer period of time than they are from knownformulations for immediate release. Preferably, the release takes placeover a time period of two to twenty four hours, of two to twenty hours,especially preferred over a time period of two to sixteen hours or twoto twelve hours, with the specifications satisfying the legal andregulating requirements.

According to the invention, formulations of medicaments that ensure sucha sustained release of the active compounds from the preparation, aredesignated as retard formulations, as sustained release formulations oras prolonged release formulations. In the context of the instantinvention, “sustained release” does not mean that the active compoundsare released from the formulation or the medicament in a pH-dependentmanner. According to the invention, the release of the active compoundsrather occurs in a pH-independent manner. According to the invention,the term “sustained release” refers to the release of active compoundsfrom a medicament over an extended period of time. It does not imply thecontrolled release at a defined place; therefore, it does not mean thatthe active compounds are either released only in the stomach, or only inthe intestine. (Of course, such a release at a defined place couldindividually be achieved by, e.g., enteric coating of the medicament.However, this presently seems not to be advantageous.)

According to the invention, “independent release” means that, given thepresence of at least two active compounds, a change of the absoluteamount of one compound does not influence the release profiles of theother compounds so that the release profiles of the other compounds arenot changed. For formulations according to the invention such anindependent release behaviour is independent of the pH value, for whichthe release is measured, or of the production process. The pHindependency particularly applies to the acidic range, i.e. for pHvalues<7. The release profile (or release behaviour) is defined as thechange of the release of the active compound from the formulation withtime, with the amount of each active compound released provided inpercents of the total amount of the active compound. The release profileis determined by known tests.

Specifically, this means that for example the release profile ofoxycodone, as it is observed for an oxycodone/naloxone-combination with12 milligrams oxycodone and 4 milligrams naloxone, does not change, if acorresponding preparation with the same formulation contains 12milligrams oxycodone, but 6 milligrams naloxone.

The independent release feature preferably refers to the situation wherepreparations of substantially equal composition are compared for therelease profile. Preparations of substantially equal composition havedifferent amounts of the active compounds but are otherwise basicallythe same with respect the components of the composition whichessentially influence the release behaviour.

If e.g. the above-mentioned preparations are compared (with the firstpreparation comprising 12 mg oxycodone and 4 mg naloxone and the secondpreparation comprising 12 mg oxycodone and 6 mg naloxone) bothpreparations, provided that they have the same total weight, willprovide for the same release profile for oxycodone and naloxone if thedifference in the naloxone amount is replaced by a component in theformulation that typically does not influence the release behaviour. Asshown in the Example section, the difference in the amount of naloxonemy be replaced by a typical pharmaceutically inert filler such aslactose without changing the release profiles.

The person skilled in the art is well aware that if the amount of theactive compound in which two preparations differ is replaced by asubstance that is essential for the release behaviour of theformulation, such as ethylcellulose or a fatty alcohol, differences inthe release behaviour may occur. Thus, the independent release featurepreferably applies to formulations that have different amounts of theactive compounds but are otherwise identical or at least highly similarwith respect to the components that essentially influence the releasebehaviour (given that formulations of the same total weight arecompared).

According to the invention, “invariant release behaviour” or “invariantrelease profile” is defined so that the percentage of the absoluteamount of each active compound released per time unit does notsignificantly change and remains sufficiently constant (and thus doesnot substantially change) if absolute amounts are changed. Sufficientlyconstant percentages mean that the percentage released per time unitdeviates from a mean value by not more than 20%, preferably by not morethan 15% and especially preferably by not more than 10%. The mean valueis calculated from six measurements of the release profile. Of course,the amount released per time unit has to satisfy the legal andregulatory requirements.

Specifically, this means for example that given an oxycodone/naloxonecombination of 12 mg oxycodone and 4 mg naloxone, during the first 4hours 25% oxycodone and 20% naloxone are released. If theoxycodone/naloxone combination instead contains 24 mg oxycodone and 8 mgnaloxone, during the first 4 hours also 25% oxycodone and 20% naloxonewill be released. In both cases the deviation will not be more than 20%from the mean value (which in this case is 25% oxycodone and 20%naloxone).

As outlined for the independent release behaviour, the invariant releasefeature also preferably refers to a situation where preparations ofsubstantially equal composition are compared. Such preparation differwith respect to the amount of the active compounds, but are of the sameor at least highly similar composition with respect to therelease-influencing components of the preparation. Typically, thedifference in the amount of an active compound will be replaced by theamount of a pharmaceutical inert excipient which does not substantiallyinfluence the release behaviour of the preparation. Such apharmaceutical excipient may be lactose, which is a typical filler inpharmaceutical preparations. The person skilled in the art is well awarethat the invariant release feature may not apply to preparations wherethe difference in the amount of an active compound is replaced bysubstances that are known to essentially influence the release behaviourof the preparation, such as ethylcellulose or fatty alcohols.

In the Example section it is set out that if one preparation comprises20 mg oxycodone and 1 mg naloxone or 20 mg oxycodone and 10 mg naloxone,with the difference in naloxone being replaced by lactose, that the twopreparations of identical weight provide for the same release profiles,so that they exhibit a sustained, invariant and independent releasebehaviour.

According to the invention “storage stable” or “storage stability” meansthat upon storage under standard conditions (at least two years at roomtemperature and usual humidity) the amounts of the active compounds of amedicament formulation do not deviate from the initial amounts by morethan the values given in the specification or the guidelines of thecommon Pharmacopoeias. According to the invention, storage stabilityalso means that a preparation produced according to the invention can bestored under standard conditions (60% relative humidity, 25° C.) as itis required for admission to the market.

According to the invention, “storage stable” or “time stable” also meansthat after storage under standard conditions the active compounds showrelease profiles as they would upon immediate use without storage.According to the invention, the admissible fluctuations with respect tothe release profile are characterized in that the amount released pertime unit fluctuates by no more than 20%, preferably no more than 15%and especially preferably no more than 10%, with respect to a meanvalue. The mean value is calculated from six measurements of the releaseprofile.

Preferably, the release of the active compounds from a sustained releaseformulation is determined by the Basket Method according to USP at pH1.2 or pH 6.5 with HPLC. Storage stability is preferably determined bythe Basket Method according to USP at pH 1.2 with HPLC.

According to the invention, a “non-swellable” or “substantiallynon-swellable” diffusion matrix is a matrix formulation for which therelease of the active compounds is not influenced (or at least not to arelevant degree) by swelling of the matrix (particularly in thephysiological fluids of the relevant target sites in the patient'sbody).

According to the invention, the term “substantially non-swellable”diffusion matrix also refers to a matrix whose volume will increase byapproximately 300%, preferably by approximately 200%, more preferably byapproximately 100%, by approximately 75% or by approximately 50%, evenmore preferably by approximately 30% or by approximately 20% and mostpreferably by approximately 15%, by approximately 10%, by approximately5% or by approximately 1% in aqueous solutions (and particularly in thephysiological fluids of the relevant target sites in the patient'sbody).

In the context of the present invention, “agonist” or “analgesic” alwaysrefers to oxycodone. In the context of the present invention“antagonist” always refers to naloxone.

Preparations produced according to the invention can be applied orally,nasally, rectally and/or by inhalation for use in pain therapy.According to the invention, parenteral application is not envisaged.Especially preferred is a formulation for oral application.

Even though this might not be expressly stated, the term “agonist” or“antagonist” always comprises pharmaceutical acceptable and equallyacting derivatives, salts and the like. If, for example, oxycodone ornaloxone is mentioned, this also comprises, besides the free base, theirhydrochloride, sulfate, bisulfate, tatrate, nitrate, citrate,bitratrate, phosphate, malate, maleate, hydrobromide, hydrojodide,fumarate, succinate and the like.

According to the invention, agonists and antagonists are formulated in away that they are released from the resulting pharmaceutical preparationin a sustained, independent and invariant manner. This does not meanthat the antagonist is in excess compared to the agonist. On thecontrary, it is preferred that in formulations comprising anagonist/antagonist combination, that show a release profile inaccordance with the invention, the agonist is in excess compared to theantagonist.

The excess of the agonist is defined based on the amount of the unitdosage of the antagonist present in the combination preparation. Theextent of the excess of the opioid agonist is usually given in terms ofthe weight ratio of agonist to antagonist.

In the case of oxycodone and naloxone, preferred weight ratios ofagonist to antagonist lie within a weight ratio range of 25:1 atmaximum, especially preferred are the weight ratio ranges 15:1, 10:1,5:1, 4:1, 3:1, 2:1 and 1:1.

The absolute amounts of agonist and antagonist to be used depend on thechoice of the active compounds. According to the invention, care has tobe taken that agonist and antagonist are released from thepharmaceutical preparation that has been formulated for sustainedrelease, only in an independent and invariant manner.

If oxycodone and naloxone are used for a combination preparation,preferably between 10 and 150 mg, especially preferably between 10 and80 mg of oxycodone (typical amounts for use) and preferably between 1and 50 mg naloxone per unit dosage are used.

In other preferred embodiments of the invention, the preparations maycomprise between 5 and 50 mg of oxycodone, between 10 and 40 mg ofoxycodone, between 10 and 30 mg of oxycodone or approximately 20 mg ofoxycodone. Preferred embodiments of the invention may also comprisepreparations with between 1 and 40 mg naloxone, 1 and 30 mg naloxone, 1and 20 mg naloxone or between 1 and 10 mg naloxone per unit dosage.

According to the invention, the ratio between oxycodone and naloxone hasto be chosen in such a way that release profiles for both activesubstances in accordance with the invention are guaranteed and that theagonist can display its analgesic effect while the amount of theantagonist is chosen in such a way that habituation- oraddiction-promoting effects and side effects of the agonist are reducedor abolished, without (substantially) affecting the analgesic effect ofthe agonist. According to the invention, development of habituation andaddiction as well as obstipation and breath depression are to beconsidered as side effects of analgesically effective opioid agonists.

According to the invention, generally common formulations can be used,given that these formulations ensure that the active compounds arereleased from the preparation in a sustained, independent and invariantmanner. According to the invention, those formulations have to be chosensuch that the active compounds are storage stable.

Matrix-based retardation formulations may preferably be used asformulations that provide a release of agonist and antagonist inaccordance with the invention. According to the invention, especiallypreferred are formulations based on a substantially non-swellablediffusion matrix. At the moment, formulations with an erosive matrix ora swellable diffusion matrix are not preferred.

According to the invention, the matrix that provides the sustainedrelease of the active compounds, has to be chosen in such a way that therelease of the active compounds occurs in a sustained, independent andinvariant manner. Preferably such matrices comprise polymers based onethylcellulose, with ethylcellulose being an especially preferredpolymer. Specifically preferred are matrices comprising polymers as theyare available on the market under the trademark Surelease®. Particularlypreferred is the use of Surelease®E-7-7050

Formulations with a release behaviour according to the inventioncomprise particularly matrices that comprise ethylcellulose and at leastone fatty alcohol as the components that essentially influence therelease characteristics of the matrix. The amounts of ethylcellulose andthe at least one fatty alcohol may significantly vary so thatpreparations with different release profiles may be achieved. Eventhough the inventive preparations usually will comprise both of theafore-mentioned components, in some cases it may be preferred that thepreparations comprise only ethylcellulose or the fatty alcohol(s) as therelease determining components.

Matrices based on polymethacrylate (as, e.g. Eudragit®RS30D andEudragit®RL30D) or matrices which comprise relevant amounts ofwater-swellable material, especially of hydroxyalkyl cellulose derivatessuch as HPMC, are presently preferably avoided according to theinvention.

Matrices that are in accordance with the invention can be used toproduce preparations that release active compounds in a sustained,independent and invariant manner and that release equal amounts of theactive compounds per time unit. Specifically, this means that in thecase of a oxycodone/naloxone combination containing 12 mg oxycodone und4 mg naloxone, 25% oxycodone and 25% naloxone are released within thefirst 4 hours. Correspondingly, in the case of a oxycodone/naloxonecombination containing 24 mg oxycodone and 8 mg naloxone, 25% oxycodoneand 25% naloxone are released during the first 4 hours, with thedeviation in both cases being no more than 20% of the mean value (whichin this case is 25% oxycodone or naloxone).

Such an equal release behaviour for both active compounds may bedesirable for medical aspects.

A preferred embodiment of the invention relates to preparations thatrelease 1% to 40%, preferably 5% to 35%, more preferably between 10% and30% and even more preferably between 15% and 25% of oxycodone and/ornaloxone after 15 minutes. In other preferred embodiments of theinvention, 15% to 20%, 20% to 25%, approximately 15%, approximately 20%or approximately 25% of oxycodone and/or naloxone are released after 15minutes.

Another preferred embodiment of the invention relates to preparationsthat release between 25% to 65%, preferably between 30% to 60%, morepreferably between 35% to 55% and even more preferably between 40% to50% of oxycodone and/or naloxone after one hour. Preferred embodimentsof the invention also relate to preparations that release between 40% to45%, 45% to 50%, approximately 40%, approximately 45% or approximately50% of oxycodone and/or naloxone after one hour.

Yet another preferred embodiment of the invention relates topreparations that release between 40% to 80%, preferably between 45% to75%, more preferably between 45% to 70% and even more preferably between45% to 50%, 50% to 55%, 55% to 60%, 60% to 65% or 65% to 70% ofoxycodone and/or naloxone after 2 hours. Preferred embodiments alsocomprise preparations that release approximately 45%, approximately 50%,approximately 55%, approximately 60%, approximately65% or approximately70% of oxycodone and/or naloxone after 2 hours.

One preferred embodiment of the invention relates to preparations thatrelease 70% to 100%, preferably between 75% to 95%, more preferablybetween 80% to 95%, and even more preferably between 80% and 90% ofoxycodone and/or naloxone after 4 hours. Preferred embodiments of theinvention also relate to preparations that release between 80% to 85%,85% to 90%, approximately 80%, approximately 85% or approximately 90% ofoxcodone and/or naloxone after 4 hours. One preferred embodiment of theinvention also relates to preparations that release between 70% to 100%,preferably between 75% to 100%, more preferably between 80% to 95% andeven more preferably between 80% to 85%, between 85% to 90% or between90% to 95% of oxycodone and/or naloxone after 7 hours. Preferredembodiments of the invention also relate to preparations that releaseapproximately 80%, approximately 85%, approximately 90% or approximately95% of oxycodone and/or naloxone after 7 hours.

Yet another preferred embodiment of the invention relates topreparations that release between 85% to 100%, preferably between 90% to100%, more preferably between 95% to 100% and even more preferablyapproximately 95% or 100% of oxycodone and/or naloxone after 12 hours.

According to the invention, formulations that provide a release of theactive compounds in accordance with the invention may comprise, besidesthe matrix forming polymers, fillers and additional substances, such asgranulating aids, lubricants, dyes, flowing agents and plasticizers.

Lactose, glucose or saccharose, starches and their hydrolysates,microcrystalline cellulose, cellatose, sugar alcohols such as sorbitolor mannitol, polysoluble calcium salts like calciumhydrogenphosphate,dicalcium- or tricalciumphosphat may be used as fillers.

Povidone may be used as granulating aid.

Highly-disperse silica (Aerosil®), talcum, corn starch, magnesium oxideand magnesium- or calcium stearate may preferably be used as flowingagents or lubricants.

Magnesium stearate and/or calcium stearate can preferably be used aslubricants. Fatty acids like stearic acid, or fats like hydrated castoroil can also preferably be used.

Polyethylene glycols and fatty alcohols like cetyl and/or stearylalcohol and/or cetostearyl alcohol can also be used as additionalsubstances that influence retardation.

If fillers and additional substances such as dyes and the mentionedlubricants, flowing agents and plasticizers are used, care has to betaken that according to the invention only such combinations togetherwith the matrix forming substance and/or the matrix forming substancesare used, which ensure release profiles of the active compounds inaccordance with the invention.

All these additional components of the formulations will be chosen insuch a way that the release matrix receives the character of asubstantially non-water- or non-buffer-swellable and non-erosivediffusion matrix.

According to the invention, a formulation is especially preferred thatcomprises ethylcellulose or Surelease® E-7-7050 as a matrix-buildingsubstance, stearyl alcohol as fatty alcohol, magnesium stearate aslubricant, lactose as filler and povidone as a granulating aid.

Preparations in accordance with the invention can be produced as allcommon application forms which, on principle, are suitable forretardation formulations and which ensure that the active compounds arereleased in a manner in accordance with the invention. Especiallysuitable are tablets, multi-layer tablets and capsules. Additionalapplication forms like granules or powders can be used, with only thoseapplications forms being admissible that provide a sufficientretardation and a release behaviour in accordance with the invention.

Pharmaceutical preparations may also comprise film coatings. However, ithas to be ensured that the film coatings do not negatively influence therelease properties of the active compounds from the matrix and thestorage stability of the active compounds within the matrix. Such filmcoatings may be colored or may comprise a initial dosage of the activecompounds if required. The active compounds of this initial dosage willbe immediately released so that the therapeutically effective bloodplasma level is reached very quickly.

Pharmaceutical preparations or preliminary stages thereof which are inaccordance with the invention can be produced by build-up or break-downgranulation. A preferred embodiment is the production by spraygranulation with subsequent drying of the granules. Another preferredembodiment is the production of granules by build-up granulation in adrum or on a granulating disk. The granules may then be pressed intoe.g. tablets using appropriate additional substances and procedures.

The person skilled in the art is familiar with granulating technology asapplied to pharmaceutical technology. The embodiment examples (seebelow) disclose specific embodiments of the invention. However, it iswell within the scope of the person skilled in the art to adapt theparameters of the process in order to achieve specific purposes.

Production of pharmaceutical preparations or preliminary stages thereof,which are in accordance with the invention, by extrusion technology isespecially advantageous. In one preferred embodiment, pharmaceuticalpreparations or preliminary stages thereof are produced by meltextrusion with co- or counter-rotating extruders comprising two screws.Another preferred embodiment is the production by means of extrusion,with extruders comprising one or more screws. These extruders may alsocomprise kneading elements.

Extrusion is also a well-established production process inpharmaceutical technology and is well known to the person skilled in theart. The person skilled in the art is well aware that during theextrusion process, various parameters, such as the feeding rate, thescrew speed, the heating temperature of the different extruder zones (ifavailable), the water content, etc. may be varied in order to produceproducts of the desired characteristics. The Example section providesfor numerous examples of preparations according to the invention thathave been produced by extrusion.

The aforementioned parameters will depend on the specific type ofextruder used. During extrusion the temperature of the heating zones, inwhich the components of the inventive formulation melt, may be between40 to 120° C., preferably between 50 to 100° C., more preferably between50 to 90° C., even more preferably between 50 to 70° C. and mostpreferably between 50 to 65° C., particularly if counter-rotating twinscrew extruders (such as a Leistritz Micro 18 GGL) are used. The personskilled in the art is well aware that not every heating zone has to beheated. Particularly behind the feeder where the components are mixed,cooling at around 25° C. may be necessary. The screw speed may varybetween 100 to 500 revolutions per minute (rpm), preferably between 100to 250 rpm, more preferably between 100 to 200 rpm and most preferablyaround 150 rpm, particularly if counter-rotating twin screw extruders(such as a Leistritz Micro 18 GGL) are used. The geometry and thediameter of the nozzle may be selected as required. The diameter of thenozzle of commonly used extruders typically is between 1 to 10 mm,preferably between 2 to 8 mm and most preferably between 3 to 5 mm. Theratio of length versus diameter of the screw of extruders that may beused for production of inventive preparations is typically around 40:1.

Generally, the temperatures of the heating zones have to be selectedsuch that no temperatures develop that may destroy the pharmaceuticallyactive compounds. The feeding rate und screw speed will be selected suchthat the pharmaceutically active compounds are released from thepreparations produced by extrusion in a sustained, independent andinvariant manner and are storage stable in the matrix. If e.g. thefeeding rate is increased, the screw speed may have to be increasedcorrespondingly to ensure the same retardation.

The person skilled in the art knows that all the aforementionedparameters depend on the specific production conditions (extruder type,screw geometry, number of components etc.) and may have to be adaptedsuch that the preparations produced by extrusion provide for asustained, independent and invariant release as well as for theafore-mentioned storage stability.

The person skilled in the art can infer from the Examples (see below)that by changing the parameters during extrusion and by changing thecomposition with respect to the compounds that are substantiallyresponsible for the release behaviour of the preparations, preparationswith different release profiles may be obtained. Thus, the presentinvention allows to first produce a preparation with a desired releaseprofile for oxycodone and naloxone by e.g. varying the amount of fattyalcohols or the matrix-forming polymer ethylcellulose as well asproduction parameters such as temperature, screw speed (duringextrusion) or pressure power during tablet production.

Once a preparation with the desired release profile has been obtained,the inventive preparations according to the invention allow the personskilled in the art to change the amounts of the preparations withrespect to the active compounds as outlined above. Preparationscomprising different amounts of the active compounds but of otherwisesubstantially equal composition, however, will then provide for thefeatures of sustained, invariant and independent release.

The Example section therefore discloses numerous examples showing thatpreparations with different release profiles may be obtained by changingthe amount of e.g. ethylcellulose. Other examples show that once apreparation has been established with desired release profiles, thechange in the amount of naloxone will not influence the releasebehaviour of such preparations if the difference in the amount of theactive compound is replaced by pharmaceutically inert excipients such aslactose.

Examples that display highly advantageous embodiments of the inventionare set out below. Additionally examples are given that emphasize theadvantages of preparations according to the invention compared to commonformulations. The examples are not to be interpreted as limiting thepossible embodiments of the invention.

EXAMPLE 1 Production of Tablets with Different Oxycodone/NaloxoneAmounts in a Non-Swellable Diffusion Matrix by Spray Granulation

The following amounts of the listed components were used for theproduction of oxycodone/naloxone tablets according to the invention.Preparation (designation) Oxy/Nal-0 Oxy/Nal-5 Oxy/Nal-10 oxycodone HCl 20.0 mg  20.0 mg  20.0 mg naloxone HCl —  5.0 mg  10.0 mg Lactose FlowLac 100 59.25 mg 54.25 mg 49.25 mg Povidone 30  5.0 mg  5.0 mg  5.0 mgSurelease ®  10.0 mg  10.0 mg  10.0 mg solid material solid materialsolid material Stearyl alcohol  25.0 mg  25.0 mg  25.0 mg Talcum  2.5 mg 2.5 mg  2.5 mg Mg-Stearate  1.25 mg  1.25 mg  1.25 mg

The Surelease® E-7-7050 polymer mixture used had the followingcomposition. Surelease ® Ethylcellulose 20 cps DibutylsebacateAmmoniumhydroxide Oleic acid Siliciumdioxide Water

For the production of tablets oxycodone HCl, naloxone HCl, Povidone 30and Lactose Flow Lac 100 were mixed in a tumbling mixer (Bohle) andsubsequently spray-granulated with Surelease® E-7-7050 in a fluidizedbath granulating device (GPCG3). The material was sieved over a Comill1.4 mm sieve. An additional granulation step was carried out with meltedfatty alcohol in a high-shear mixer (Collette). All tablet coresproduced by this approach had a weight of 123 mg, based on drysubstance.

EXAMPLE 2 Production of Tablets with Oxycodone and Naloxone in aNon-Swellable Diffusion Matrix by Extrusion

The following amounts of the listed components were used for theproduction of the oxycodone/naloxone tablets according to the invention.Preparation (designation) Oxy/Nal-Extr oxycodone HCl   20 mg naloxoneHCl   10 mg Kollidon 30    6 mg Lactose Flow Lac 100 49.25 mgEthylcellulose 45 cpi   10 mg Stearyl alcohol   24 mg Talcum  2.5 mgMg-Stearate  1.25 mg

The listed amounts of oxycodone HCl, naloxone HCl, ethylcellulose 45cpi, Povidone 30, stearyl alcohol and Lactose Flow Lac 100 were mixed ina tumbling mixer (Bohle). This mixture was subsequently extruded with acounter-rotating twin screw extruder of the type Micro 18 GGL (LeistritzAG, Nürnberg, Germany). The temperature of heating zone 1 was 25° C., ofheating zone 2, 50° C., of heating zones 3 to 5, 60° C., of heatingzones 6 to 8, 55° C., of heating zone 9, 60° C. and of heating zone 10,65° C. The screw rotating speed was 150 revolutions per minute (rpm),the resulting melt temperature was 87° C., the feed rate was 1.5 kg/hand the diameter of the nozzle opening was 3 mm. The extruded materialwas sieved with a Frewitt 0.68×1.00 mm sieve. The grinded extrudate wasthen mixed with talcum and magnesium stearate that had been added over a1 mm hand sieve and was subsequently pressed into tablets. The extruderhas a screw geometry, as shown in FIG. 1.

In comparison to the oxycodone/naloxone tablets which also have theSurelease®-based non-swellable diffusion matrix produced by spraygranulation (see Example 1), extruded preparations comprise lesscomponents.

Example 3 Release Profile of the Oxycodone/Naloxone Tablets from Example1

The release of the active compounds was measured over a time period of12 hours, applying the Basket Method according to USP at pH 1.2 usingHPLC. Tablets Ox/Nal-0, Ox/Nal-5 and Ox/Nal-10 were tested.

One recognizes from FIG. 2 and the values listed in the Table that inthe case of a non-swellable diffusion matrix based on Surelease®, therelease rates of different oxycodone amounts, independent of thenaloxone amount, remain equal (invariant). Correspondingly, invariantrelease profiles are observed for naloxone at different done amounts.Ox/Nal- Time OxNal-0 5-O Ox/Nal-5-N Ox/Nal-10-O Ox/Nal-10-N (min) OxyOxy Nal Oxy Nal 0 0 0 0 0 0 15 26.1 24.9 23.5 22.8 24.1 120 62.1 63 6157.5 60.2 420 91.7 94.5 91.9 89.4 93.5 720 98.1 99.6 96.6 95.7 100.6

The release values refer to oxycodone or naloxone (line 2) and are givenas percentages. The mean value for the release of naloxone at e.g. 420min is 92,7%. The maximal deviation at 420 min is 1%. Oxy and Nal standfor oxycodone and naloxone and indicate the active compound which hasbeen measured.

EXAMPLE 4 Release Profile of Oxycodone/Naloxone Tablets from Example 2at Different pH-Values

The release of active compounds from the tablets was measured over atime period of 12 hours at pH 1.2 or for 1 hour at 1.2 and subsequentlyfor 11 hours at pH 6.5. Release rates were determined by the basketmethod according to USP using HPLC.

The following release rates were measured for 12 hours at pH 1.2: TimeOxy/Nal-Extr-1,2-O Oxy/Nal-Extr-1,2-N (min) Oxy Nal 0 0 0 15 24.1 24.0120 62.9 63.5 420 92.9 93.9 720 96.9 98.1

The following release rates were measured for 1 hour at pH 1.2 and 11hours at pH 6.5: Time Oxy/Nal-Extr-6,5-O Oxy/Nal-Extr-6,5-N (min) OxyNal 0 0 0 60 48.1 49.2 120 65.0 64.7 240 83.3 81.8 420 94.1 92.3

The release rates refer to oxycodone and naloxone (line 2) and are givenas percentages. Oxy and Nal stand for oxycodone and naloxone andindicate the active compound measured.

The comparison of the values given in the Tables of Example 4 and theTable of Example 3 make clear that independent of the productionprocess, active compounds are released in equal amounts from thepreparations. For example, 89.4% of oxycodone is released fromspray-granulated tablets (Ox/Nal-10-tablets, see Example 3) at 420minutes, while 92.9% is released from extruded tablets(Oxy/Nal-Extr-1.2-O, Example 4) at 420 minutes. The release of oxycodonefrom extruded tablets thus deviates by 1.1% from the mean value of therelease of oxycodone from spray-granulated tablets (91.9% at 420minutes). 93.5% of naloxone is released from spray-granulated tablets(Ox/Nal-10-tablets, see Example 3) at 420 minutes, while 93.9% isreleased from extruded tablets (Oxy/Nal-Extr.-1.2-O, Example 4) at 420minutes. The release of naloxone from extruded tablets thus deviates by1.3% from the mean value of the release of naloxone fromspray-granulated tablets (92.7% at 420 minutes).

Moreover, one can infer from a comparison of the values of the Tables ofExample 4 and from FIGS. 3 a and 3 b that independent of the pH value atwhich the release rates have been measured the release of oxycodone andnaloxone remain equal and invariant.

EXAMPLE 5 Comparative Example: Release Behaviour of Valoron® Tablets

The release of the active substances from tablets was monitored over atime period of 7 hours. Valoron® tablets with 50 mg tilidine and 4 mgnaloxone (Ti/Nal-50/4) or 100 mg tilidine and 8 mg naloxone(Ti/Nal-100/8) or 150 mg tilidine and 12 mg naloxone (Ti/Nal-150/12)were tested by the Basket Method according to USP for 1h at pH 1.2 andthen for additional 6 h at pH 6.5 using HPLC.

One recognizes from FIGS. 4A and 4B and the values listed in the Tablethat in case of a swellable (and possibly erosive) diffusion matrix withrelevant amounts of HPMC, the release of different amounts of tilidinevaries significantly and is not invariant for different amounts ofnaloxone. This applies in turn to naloxone. This means that for this pHthe release of the active compounds is not independent of each other.Ti/Nal- Ti/Nal- Ti/Nal- Ti/Nal- Ti/Nal- Ti/Nal- Time 50/4-T 50/4-N100/8-T 100/8-N 150/12-T 150/12-N (min) Til Nal Til Nal Til Nal 0 0 0 00 0 0 60 37.2 27.6 33.9 27.3 29.9 23.3 120 47.6 31.7 46.5 33.4 41.5 28.5180 54.7 37.4 55 41.2 48.2 35 240 59.7 44 68.2 59.5 54.5 40.1 300 65.250.6 82.6 72.9 60.5 47.5 360 70.3 58 85.7 82.7 67.2 56.4 420 74.2 60.893.1 90.9 84.9 78.9

The release values refer to tilidine or naloxone (line 2) and are givenas percentages. The mean value for the release of naloxone at e.g. 420min is 78,87%. The maximal deviation at 420 min is 20,4%. Til und Nalstand for tilidine and naloxone and indicate the active compound tested.

EXAMPLE 6 Structure Comparison of Tablets of Examples 1 and 2 withValoron® N Tablets by Electron Microscopy

For electron microscopy tablets were used that comprised 20 mg oxycodoneand 10 mg naloxone and were produced either by spray granulationaccording to Example 1 (Ox/Nal-10) or by extrusion according to Example2 (Oxy/Nal-Extr). Additionally, a Valoron® N tablet with 100 mg Tilidinand 8 mg Naloxone was used. FIGS. 5A and 5B show differentmagnifications of scanning electron microscopy pictures of aOx/Nal-10-tablet with a formulation according to the invention which wasproduced by spray granulation. FIGS. 6A and 6B show differentmagnifications of scanning electron microscopy pictures of aOxy/Nal-Extr-tablets with a formulation according to the invention,which was produced by extrusion. FIGS. 7A and 7B show scanning electronmicroscopy pictures of the Valoron® N-tablet.

From a comparison of the figures one can clearly see that tablets with aformulation according to the invention have a surface which issubstantially finer and more homogeneously structured and which showsfewer cracks than the Valoron® tablet, regardless of whether the tabletshave been produced by spray granulation or extrusion. The structuraldifference is possibly the reason for the different release behavioursof the different preparations.

EXAMPLE 7 Production of Tablets with Different Oxycodone/NaloxoneAmounts in a Non-Swellable Diffusion Matrix by Extrusion

The following amounts of the listed components were used for theproduction of oxycodone/naloxone tablets according to the invention.Preparation (designation) OxN20/ OxN20/ OxN20/ OxN20/ 1-Extr-A 1-Extr-B1-Extr-C 10-Extr-A Oxycodone   20 mg   20 mg   20 mg   20 mg HClNaloxone HCl    1 mg    1 mg    1 mg   10 mg Lactose Flow 58.25 mg 58.25mg 58.25 mg 49.25 mg Lac 100 Kollidon ® 30    6 mg    6 mg    6 mg    6mg Ethylcellulose   10 mg   10 mg   10 mg   10 mg Stearly alcohol   24mg   24 mg   24 mg   24 mg Talcum 1.25 mg  1.25 mg  1.25 mg  1.25 mgMg-Stearate  2.5 mg  2.5 mg  2.5 mg  2.5 mg

Extrusion was performed as described above (Example 2) with thefollowing parameters: OxN20/1-Extr-A: temperature: 55-63° C. rpm(screw): 150 rpm feeding rate: 1.5 kg/h OxN20/1-Extr-B: temperature:55-63° C. rpm (screw): 155 rpm feeding rate: 1.5 kg/h OxN20/1-Extr-C:temperature: 55-63° C. rpm (screw): 1505 rpm feeding rate: 1.5 kg/hOxN20/10-Extr-A: temperature: 55-63° C. rpm (screw): 160 rpm feedingrate: 1.75 kg/h

Tablet production was performed with a common tabletting device with thefollowing parameters: OxN20/1-Extr-A: rpm: 40 rpm Pressure power: 9 kNOxN20/1-Extr-B: rpm: 42 rpm Pressure power: 8.9 kN OxN20/1-Extr-C: rpm:36 rpm Pressure power: 9 kN OxN20/10-Extr-A: rpm: 36 rpm Pressure power:7.5 kN

The release of the active compounds was measured over a time period of12 hours, applying the Basket Method according to USP at pH 1.3 usingHPLC. Tablets OxN20/1-Extr-A, OxN20/1-Extr-B, OxN20/1-Extr-C andOxN20/10-Extr-A were tested.

One recognizes from the values listed in the Table that in the case of anon-swellable diffusion matrix based on ethylcellulose, the releaserates of different naloxone amounts, independent of the oxycdone amount,remain substantially equal. Correspondingly, the preparations providefor an independent and invariant release of the active compounds.OxN20/1- OxN20/1- OxN20/1- OxN20/10- Time Extr-A Extr-B Extr-C Extr-A(min) Oxy Nal Oxy Nal Oxy Nal Oxy Nal 0 0 0 0 0 0 0 0 0 15 21.2 25.821.7 21.1 19.7 19.3 23.3 24.3 120 56.6 53.8 58.8 57.3 57.7 56.2 64.566.9 420 87.2 84.5 94.2 92.6 93.7 91.5 92.7 96.3 720 99.7 96.8 100.1 98100.6 97.5 93.6 97.4

The release values refer to oxycodone or naloxone (line 2) and are givenas percentages. The mean value for the release of naloxone at e.g. 420min is 92.3%. The maximal deviation at 420 min is 7.4%. Oxy and Nalstand for oxycodone and naloxone and indicate the active compound whichhas been measured.

Thus, once a preparation with the desired release profile has beendeveloped, one can change the amount of the active compounds withoutsignificantly changing the release profiles of the active compounds. Thepreparations comprising different amounts of the active compounds stillprovide for a sustained, independent an invariant release of the activecompounds.

EXAMPLE 8 Production of Tablets with Oxycodone/Naloxone in aNon-Swellable Diffusion Matrix by Extrusion

In the following example it is set out that using formulations accordingto the present invention, preparations comprising oxycodone and naloxonewith particular release behaviours may be obtained.

The following amounts of the listed components were used for theproduction of oxycodone/naloxone tablets according to the invention.Preparation OxN20/1- OxN20/1- OxN20/10- OxN20/10- OxN20/10- OxN20/10-(designation) Extr-D Extr-E Extr-B Extr-C Extr-D Extr-E oxycodone HCl  20 mg   20 mg   20 mg   20 mg   20 mg   20 mg naloxone HCl    1 mg   1 mg   10 mg   10 mg   10 mg   10 mg Lactose Flow 56.25 mg 56.25 mg54.25 mg 65.25 mg 60.25 mg 55.25 Lac 100 Kollidon ® 30    7 mg    6 mg   6 mg  7.25 mg  7.25 mg  7.25 mg Ethylcellulose   11 mg   12 mg   10mg   12 mg   12 mg   12 mg Stearyl alcohol   24 mg   24 mg   24 mg 28.75mg 28.75 mg 28.75 mg Talcum  1.25 mg  1.25 mg  1.25 mg  1.25 mg  1.25 mg 1.25 mg Mg-Stearate  2.5 mg  2.5 mg  2.5 mg  2.5 mg  2.5 mg  2.5 mg

Extrusion was performed as described above (Example 2) with thefollowing parameters: OxN20/1-Extr-D: temperature: 55-63° C. rpm(screw): 150 rpm feeding rate: 1.5 kg/h OxN20/1-Extr-E: temperature:55-63° C. rpm (screw): 150 rpm feeding rate: 1.5 kg/h OxN20/10-Extr-B:temperature: 55-63° C. rpm (screw): 160 rpm feeding rate: 1.75 kg/hOxN20/10-Extr-C: temperature: 55-63° C. rpm (screw): 160 rpm feedingrate: 1.75 kg/h OxN20/10-Extr-D: temperature: 55-63° C. rpm (screw): 150rpm feeding rate: 1.5 kg/h OxN20/10-Extr-E: temperature: 55-63° C. rpm(screw): 150 rpm feeding rate: 1.5 kg/h

Tablet production was performed with a common tabletting device with thefollowing parameters: OxN20/1-Extr-D: rpm: 39 rpm Pressure power: 11 kNOxN20/1-Extr-E: rpm: 39 rpm Pressure power: 10.5 kN OxN20/10-Extr-B:rpm: 36 rpm Pressure power: 9.5 kN OxN20/10-Extr-C: rpm: 36 rpm Pressurepower: 7.8 kN OxN20/10-Extr-D: rpm: 39 rpm Pressure power: 9 kNOxN20/10-Extr-E: rpm: 39 rpm Pressure power: 7.5 kN

The release of the active compounds was measured over a time period of12 hours, applying the Basket Method according to USP at pH 1.2 usingHPLC. Tablets OxN20/1-Extr-D, OxN20/1-Extr-E, OxN20/10-Extr-B,OxN20/10-Extr-C, OxN20/10-Extr-D and OxN20/10-Extr-E were tested.OxN20/1- OxN20/1- OxN20/10- OxN20/10- OxN20/10- OxN20/10- Time Extr-DExtr-E Extr-B Extr-C Extr-D Extr-E (min) Oxy Nal Oxy Nal Oxy Nal Oxy NalOxy Nal Oxy Nal 0 0 0 0 0 0 0 0 0 0 0 0 0 15 16.6 16.2 17.4 17.2 26.126.8 21.8 21.9 18.5 18.2 18.4 18.2 120 47.6 46.9 49.6 49.7 71.1 73.061.2 61.8 52.8 52.8 53.3 53.3 420 82.7 84.5 84.6 85.7 94.3 96.6 93.294.7 86.3 86.3 87.2 88.2 720 95 97 95.2 95.8 94.9 97.9 96.4 97.9 94.894.8 95.7 96.5

The release values refer to oxycodone or naloxone (line 2) and are givenas percentages. Oxy and Nal stand for oxycodone and naloxone andindicate the active compound which has been measured.

The example shows that preparations with particular release profiles maybe produced if ethylcellulose and fatty alcohols are used as thematrix-components that essentially influence the release characteristicsof the preparations. Once a preparation with desired releasecharacteristics has been obtained the amount of the active compounds maybe changed. The preparations will still provide for a sustained,independent and invariant release behaviour (see example 7).

1. A storage stable pharmaceutical preparation comprising oxycodone andnaloxone in a substantially non-swellable diffusion matrix comprisingethyl cellulose, characterized in that the active compounds are releasedfrom the preparation in a sustained, invariant and independent manner.2. Preparation according to claim 1, characterized in that oxycodoneand/or naloxone are present in the form of pharmaceutically acceptableand equally active derivatives such as the free base, salts and thelike.
 3. Preparation according to claim 2, characterized in thatoxycodone and/or naloxone are present as their hydrochloride, sulfate,bisulfate, tatrate, nitrate, citrate, bitatrate, phosphate, malate,maleate, hydrobromide, hydroiodide, fumarate or succinate. 4.Preparation according to claim 3, characterized in that oxycodone ispresent in excess referred to the unit dosage amount of naloxone. 5.Preparation according to claim 1, characterized in that naloxone ispresent in an amount range of about 1 g to about 50 mg.
 6. Preparationaccording to claim 1, characterized in that oxycodone is present in anamount range of about 10 mg to about 150 mg.
 7. Preparation according toclaim 1, characterized in that oxycodone and naloxone are present inweight ratio ranges of from about 25:1 to about 1:1.
 8. Preparationaccording to claim 7, characterized in that the preparation comprises asubstantially non-erosive diffusion matrix.
 9. Preparation according toclaim 8, characterized in that the diffusion matrix comprises at leastethylcellulose and at least one fatty alcohol as the components thatessentially influence the release behavior of the active compounds. 10.Preparation according to claim 9, characterized in that the preparationdoes not comprise relevant parts of alkaline and/or water-swellablesubstance.
 11. Preparation according to claim 10, characterized in thatthe preparation contains fillers and additional substances. 12.Preparation according to claim 11, characterized in that it comprisesmagnesium stearate, calcium stearate and/or calcium laureate and/orfatty acids.
 13. Preparation according to claim 11, characterized inthat it comprises a flowing agent selected from the group consisting ofhighly-disperse silica, talcum, corn starch, magnesium oxide andmagnesium and calcium stearate.
 14. A storage stable pharmaceuticalpreparation comprising oxycodone and naloxone in a substantiallynon-swellable diffusion matrix, characterized in that the matrix isinfluenced with respect to its substantial release characteristics byethylcellulose and at lease one fatty alcohol and that the preparationcomprises oxycodone and naloxone in a weight ratio of from about 25:1 toabout 1:1.
 15. Preparation according to claim 14, characterized in thatthe oxycodone and naloxone are present in the form of pharmaceuticallyacceptable and equally active derivatives.
 16. Preparation according toclaim 15, characterized in that oxycodone and naloxone are present ashydrochloride, sulfate, bisulfate, tatrate, nitrate, citrate, bitatrate,phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate orsuccinate.
 17. Preparation according to claim 16, characterized in thatoxycodone is present in excess referred to the unit dosage amount ofnaloxone.
 18. Preparation according to claim 17, characterized in thatoxycodone is present in an amount range of about 1 mg to about 50 mg.19. Preparation according to claim 18, characterized in that oxycodoneis present in an amount range of about 10 mg to about 150 mg. 20.Preparation according to claim 19, characterized in that preparationcomprises a substantially non-swellable and non-erosive diffusionmatrix.
 21. Preparation according to claim 20, characterized in that thediffusion matrix comprises at least ethylcellulose and at least onefatty alcohol as the components that essentially influence the releasebehavior of the active compounds.
 22. Preparation according to claim 21,characterized in that the preparation does not comprise relevant partsof alkaline and/or water-swellable substance.
 23. Preparation accordingto claim 22, characterized in that the fatty alcohols comprise lauryl,myrestyl, stearyl, cetostearyl, ceryl and/or cetyl alcohol. 24.Preparation according to claim 23, characterized in that the preparationcomprises fillers and additional substances.
 25. Preparation accordingto claim 24, characterized in that it comprises magnesium stearate,calcium stearate and/or calcium laureate and/or fatty acids. 26.Preparation according to claim 24, characterized in that it comprises aflowing agent selected from the group consisting of highly-dispersesilica, talcum, corn starch, magnesium oxide, magnesium stearate andcalcium stearate.
 27. Preparation according to claim 26, characterizedin that commercially available polymer mixtures which compriseethylcellulose are used instead of ethylcellulose.
 28. Preparationaccording to claim 27, characterized in that the preparation has beenformulated for oral, nasal, rectal application or for application byinhalation.
 29. Preparation according to claim 28, characterized in thatthe preparation is in the form of a tablet, pill, capsule, granule orpowder.
 30. Preparation according to claim 29, characterized in thatpreparation or precursors thereof are produced by build-up and/orbreak-down granulation.
 31. Preparation according to claim 29,characterized in that the preparation or precursors thereof are producedby extrusion.
 32. Preparation according to claim 31, characterized inthat the preparation can be stored over a period of at least 2 yearsunder standard conditions (60% relatively humidity, 25° C.) inaccordance with admission guidelines.
 33. A preparation according toclaim 6, characterized in that oxycodone is present in an amount rangeof from about 10 mg to about 80 mg.
 34. A preparation according to claim7, characterized in that oxycodone and naloxone are present in weightratio ranges of from about 5:1 to about 1:1.
 35. A preparation accordingto claim 10, characterized in that the preparation does not compriserelevant parts of derivatives of acrylic acid and/or hydroxy alkylcelluloses.
 36. A preparation according to claim 11, further comprisingone or more materials from the group consisting of lubricants, flowingagents, plasticizers and the like.
 37. A preparation according to claim12, characterized in that it comprises stearic acid.
 38. A storagestable pharmaceutical preparation according to claim 14, comprisingoxycodone and naloxone in a substantially non-swellable diffusionmatrix, characterized in that the matrix is influenced with respect toits substantial release characteristics by ethylcellulose and at leaseone fatty alcohol and that the preparation comprises oxycodone andnaloxone in a weight ratio of from about 5:1 to about 1:1.
 39. Apreparation according to claim 19, characterized in that oxycodone ispresent in an amount range of about 10 mg to about 80 mg.
 40. Apreparation according to claim 22, characterized in that the preparationdoes not comprise relevant parts of derivatives of acrylic acid and/orhydroxy alkyl celluloses.
 41. A preparation according to claim 24,further comprising one or more materials from the group consisting oflubricants, flowing agents, plasticizers and the like.
 42. A preparationaccording to claim 25, characterized in that it comprises stearic acid.43. A preparation according to claim 27, characterized in that thecommercially available polymer mixture is Surelease® E-7-7050.
 44. Apreparation according to claim 15, characterized in that thepharmaceutically acceptable and equally active derivatives are thefree-base, salts and the like.